The present invention relates to the manufacture of compounds which are useful intermediates in the synthesis of compounds having valuable pharmacologic properties, particularly as antihypertensive agents.
The intermediate of interest is the (S,S) diastereoisomer of compounds of the formula ##STR2## wherein R can be hydroxy, lower alkoxy, lower alkenoxy, di(lower alkyl)amino-lower alkoxy, hydroxy-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryl-lower alkoxy, amino, lower alkylamino, di-lower alkylamino, hydroxyamino, or aryl-lower alkylamino;
R.sub.3 can be hydrogen, lower alkyl, aryl-lower alkyl, cycloalkyl containing 3 to 20 carbon atoms, or fused aryl-cycloalkyl (hereby defined as a phenyl ring fused to a cycloalkyl ring containing 3 to 7 carbon atoms);
R.sub.1, R.sub.2, R.sub.4, and R.sub.5 can be independently any of the groups listed above for R.sub.3, or alkenyl, or alkynyl;
wherein each alkenyl and alkynyl group contains 2 to 6 carbon atoms, each lower alkyl group and moiety contains 1 to 6 carbon atoms, and the groups can be substituted as described herein. The two asterisks denote the asymmetrical centers.
An intermediate of particular interest has the formula ##STR3## and is titled N-[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine. Hereafter, this configuration will be referred to as (S,S), in accordance with recognized terminology.
The free carboxylic group of compound (1) can be reacted with appropriately substituted amino compounds such as 1,2,3,4-tetrahydroisoquinoline-3-carboxylate, using standard peptide coupling techniques, to form compounds which are useful in treating hypertension. The resulting dipeptides, and their preparation from a compound having formula (2), are described in greater detail in Belgian Pat. Nos. 892,552 and 892,669 and U.S. Pat. No. 4,344,949. This U.S. patent also discloses that the particular stereochemistry shown in formula (2) above must be present in the dipeptide for biological activity.
One efficacious technique of obtaining the desired stereochemical configuration in the dipeptide is using an intermediate having formula (1) in the (S,S) stereochemical configuration. However, this technique is inefficient, in part because reactions to form compound (1) in its (S,S) configuration will form corresponding amounts of either the (R,S) or (S,R) diastereoisomer, depending on the configuration of the reactants, and separation of the (S,S) diastereoisomer has heretofore been low-yielding and tedious. Thus, it is desirable to be able to form the diastereoisomer of formula (1) by a process which is higher-yielding and less cumbersome than known processes.